Reproductive dysfunction manifested as infertility, early embryonic loss, or congenital anomalies afflicts 10- 15% of reproductive aged individuals and results in high economic and psychological costs. Many infertile males and females display impaired function of the hypothalamic-pituitary-gonadal (HPG) axis, but the precise etiology is often not known. Coordination of the HPG axis is dependent upon appropriate migration and development of hypothalamic gonadotropin releasing hormone (GnRH) neurons followed by proper GnRH synthesis and pulsatile release. Idiopathic hypogonadotropic hypogonadism (IHH) represents a naturally occurring human model of impaired GnRH action which provides insight into hypothalamic-pituitary function in reproduction. Kallmann syndrome (KS), a specific subtype of IHH, includes anosmia, as well as other neurologic deficits and congenital anomalies. Although mutations in KAL1, FGFR1, and GNRHR genes account for 20-30% of cases and digenic disease has been reported in a few families, the molecular basis for most IHH/KS cases is not well understood. Recently, we identified mutations in the chromodomain helicase DNA binding protein-7 (CHD7) and nasal embryonic LHRH factor (NELF) genes in sporadic IHH/KS patients. However, the precise phenotypic findings and segregation patterns within families for either of these genes are not known. Our overlying hypothesis is that CHD7 and NELF mutations cause autosomal dominant IHH/KS by the disruption of GnRH and olfactory neuron migration and/or by impaired expression of reproductive genes within the hypothalamus. We will test this hypothesis with the following Specific Aims: Aim 1) We will test the hypothesis that NELF or CHD7 mutations cause autosomal dominant IHH/KS. We will genotype individuals from families with mutations in either of these genes to characterize the segregation patterns and define the phenotype. To exclude digenic disease, affected individuals will be genotyped for mutations in more than one gene. Aim 2) We will test the hypothesis that both CHD7 and NELF have: A) an early embryologic function to regulate GnRH and olfactory neuron migration and; B) overexpression of human mutations will interfere with GnRH and olfactory neuron migration. In Sub Aim 2A, we will knockdown NELF and CHD7 expression in migratory neurons (GnRH neuronal cells and human olfactory neuroblasts) and chd7 expression in zebrafish to determine the effect upon neuron migration and the expression of key genes involved in neuron migration. In Sub Aim 2B, we will determine if overexpression of human NELF and CHD7 mutations in these neuronal cell lines and zebrafish affects migration and the expression of key genes involved in neuron migration. Demonstration that NELF and CHD7 mutations cause autosomal dominant disease will directly lead to improved genetic counseling. Characterization of the basic function of NELF and CHD7 will provide novel information related to the developmental control of GnRH neuron migration and reproduction. Our findings also have the potential to define more common, but less severe causes of IHH/KS and other forms of infertility.